Risk factors for oral epithelial dysplasias to become malignant: clinical implications.

There is a lack of effective clinical management of oral epithelial dysplasias to reduce their risk of malignant transformation and considerable gaps in knowledge regarding the most effective means of treating such lesions. A retrospective cohort of biopsy-confirmed oral epithelial dysplasias consecutively diagnosed in the period 1995-2014 and followed-up until 2017 was identified from pathology department files. Demographic, clinical and follow-up information was collected. Multivariate Cox proportional-hazards models were performed to evaluate sociodemographic, clinical and pathological factors associated with progression to oral squamous cell carcinoma. The study included 144 oral epithelial dysplasias, of which 42% progressed to oral cancer at the end of follow-up (21 years). Clinical aspect of the lesion was described for 77 (53.5%) of the patients. Treatment, age, grade of the lesion and diagnostic period were independent prognostic factors for progression. When considering only patients with described clinical aspect, only treatment and grade of the lesion were independently associated with cancer. The results from this non-selected retrospective cohort of oral epithelial dysplasias underscore the existing limitations of the current standard-of-care of the patients and provide novel insights on the management of these lesions with and without described clinical aspect. Well-designed, robust prospective studies, a homogenized staging system and multidisciplinary treatment guidelines are warranted.

The potential role of imaging techniques in avoiding neck dissection during salvage surgery after head and neck carcinoma treated with bioradiotherapy.

OBJECTIVE: This study aimed to evaluate the effectiveness of computed tomography and positron emission tomography-computed tomography prior to salvage surgery after head and neck carcinoma treated with bioradiotherapy and to look at the role of neck dissection in this setting. METHOD: This study was a retrospective chart review of a series of consecutive patients with locally advanced head and neck squamous cell carcinoma treated with bioradiotherapy. Radiological and pathological stages were compared to evaluate the accuracy of computed tomography and positron emission tomography-computed tomography in detecting occult neck metastasis in the context of recurrence of primary tumour. In order to assess the impact of neck dissection on survival, Kaplan-Meier survival curves after salvage surgery with and without neck dissection were derived. RESULTS: A total of 268 patients were identified, of which 22 underwent salvage surgery. The negative predictive value of computed tomography and positron emission tomography-computed tomography was excellent. Neck dissection did not represent an improvement on overall, disease specific and regional recurrence free survival (p = 0.67, p = 0.91 and p = 0.62, respectively) amongst clinically and radiologically negative necks. CONCLUSION: Conservative treatment of the neck should be considered when dealing with patients with primary site recurrence or persistent disease after bioradiotherapy without evidence of neck disease.

SEOM clinical guidelines for the treatment of head and neck cancer (2020)

Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m2 in the adjuvant setting, new approaches for HPV-related oropharyngeal cancer and new treatments with immune-checkpoint inhibitors in recurrent/metastatic disease (AU)

SEOM clinical guidelines for the treatment of head and neck cancer (2020).

Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m2 in the adjuvant setting, new approaches for HPV-related oropharyngeal cancer and new treatments with immune-checkpoint inhibitors in recurrent/metastatic disease.

Epidemiology of human papillomavirus-related oropharyngeal cancer in a classically low-burden region of southern Europe.

The incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing in some regions. Nevertheless, the epidemiology of this disease has not been extensively investigated in southern Europe. We conducted a retrospective cohort study of patients diagnosed with primary oropharyngeal cancer from 1991 to 2016. Cancer tissues underwent histopathological evaluation, DNA quality control, HPV-DNA detection and p16INK4a immunohistochemistry. Data were collected from medical records. Factors associated with HPV positivity and time trends were evaluated with multivariable Bayesian models. The adjusted prevalence of HPV-related cases in 864 patients with a valid HPV-DNA result was 9.7%, with HPV-DNA/p16INK4a double positivity being considered. HPV-related oropharyngeal cancer was likely to occur in non-smokers and non-drinkers, to be located in the tonsil or diagnosed at advanced stages. Time-trend analysis showed an increasing risk of HPV-related oropharyngeal cancer in the most recent periods (5-year period increase of 30%). This increase was highest and with a clear increasing trend only in the most recent years (2012-2016). The prevalence of HPV-related oropharyngeal cancer started to sharply increase in the most recent years in our setting, as occurred two decades ago in areas where most oropharyngeal cancer cases are currently HPV-related. Our results provide a comprehensive assessment of the epidemiological landscape of HPV-related oropharyngeal cancer in a region of southern Europe.

Immune biomarkers of response to immune-checkpoint inhibitors in head and neck squamous cell carcinoma.

Anti-programmed cell death protein 1 (PD-1) agents have become the standard of care for platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) and are currently being evaluated in various disease settings. However, despite the gain in overall survival seen in some of the clinical trials, the majority of patients display primary resistance and do not benefit from these agents. Taking into consideration the potentially severe immune-related toxicities and their high cost, the search for predictive biomarkers of response is crucial. Besides Programmed death ligand-1 (PD-L1) expression, other biomarkers such as immune infiltration, tumor mutational burden or immune-gene expression profiling have been explored, but none of them has been validated in this disease. Among these, the microbiota has recently garnered tremendous interest since it has proven to influence the efficacy of PD-1 blockade in some tumor types. With the accumulating evidence on the effect of the microbiota in HNSCC tumorigenesis and progression, the study of its potential role as a predictive immune biomarker is warranted. This review examines the available evidence on emerging immune predictive biomarkers of response to anti-PD-1/PD-L1 therapy in HNSCC, introducing the microbiota and its potential use as a predictive immune biomarker in this disease.

Nutritional changes in patients with locally advanced head and neck cancer during treatment.

OBJECTIVE: The purpose of the study is to evaluate changes in body composition and nutritional status that occur throughout the oncological treatment in head and neck cancer patients. METHODS: A prospective cohort observational study in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) that underwent treatment with induction chemotherapy (iCT) followed by chemoradiotherapy or bioradiotherapy were invited to participate. All patients had dietetic counseling from the diagnosis and a close monitoring throughout the treatment implementing nutritional support as needed. RESULTS: From June 2011 until October 2012, 20 patients were included. Nutritional and anthropometric parameters were collected at diagnosis, post iCT, after radiotherapy, 1 and 3months post radiotherapy. According to Patient Generated Subjective Global Assessment, 30% of patients were malnourished at diagnosis. After iCT there was an increase in weight, body mass index (BMI) and fat free mass (FFM) with almost complete improvement in dysphagia and odynophagia. Nevertheless a significant nutritional deterioration (p=0.0022) occurred at the end of radiotherapy with 95% of patients becoming severe or moderate malnourished. Nutritional parameters such as weight, BMI and hand grip strength also decrease significantly during treatment. CONCLUSIONS: Despite an intensive nutritional support from the diagnosis throughout the oncological treatment in advanced HNSCC cancer patients, nutritional status deteriorates during radiotherapy. Our findings suggest that iCT may help improve nutritional status by ameliorating the symptoms that limit the oral intake. This improvement in the nutritional status could contribute to minimize further deterioration. Further investigations are needed involving novel approaches to avoid nutritional deterioration.

Human papillomavirus-related oropharyngeal cancer.

High-risk human papillomavirus (HPV) is now recognised as the principal cause of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in some parts of the world. The primary risk factor for developing HPV-related OPSCC is oral HPV-infection and the majority of oral HPV-infections are acquired by oral sex. Progression into an OPSCC includes persistent infection with evasion of immune response in the microenvironment, the activation of viral early genes (E6, E7) in basal epithelial cells, the deregulation of cell cycle and the accumulation of chromosomal instability. Patients affected by HPV-related OPSCC tend to be younger and have better outcomes. This observation has lead current research to evaluate treatment de-escalation options to reduce long-term associated morbidity. Moreover, a different molecular profile for HPV-related OPSCC has been described, opening new options for targeted therapy and immunotherapy approaches. This paper comprehensively reviews our accumulated knowledge regarding the role of HPV in OPSCC spanning from infection to cancer development, including its clinical diagnosis, management and preventive strategies.

HPV knowledge gaps and information seeking by oral cancer patients.

OBJECTIVES: The incidence of human papillomavirus (HPV) positive oral squamous cell carcinoma (OSCC) continues to increase over time, challenging healthcare providers to address their patients' HPV-related concerns. MATERIALS AND METHODS: This prospective study assessed health literacy, HPV knowledge, utilization and trust in information sources among patients with incident HPV-positive or HPV-negative OSCC diagnosed at the Ohio State University from 2011 to 2015. Health literacy was assessed with a standardized scale. Additional questions evaluated HPV knowledge (including transmission, prevalence, health consequences and treatment), the frequency and type of information sources sought, and trust in those sources. RESULTS: Surveys were collected from 372 OSCC cases (HPV-positive, n=188; HPV-negative, n=184). Despite high mean health literacy scores, only 45.2% of HPV-related knowledge questions were answered correctly. HPV was known to be a sexually transmitted infection and a cause of cervical and anal cancer by 66.0%, 56.5% and 15.2%, respectively. In all domains, cases with HPV-positive OSCC were significantly more informed than HPV-negative cases (for all, p<0.01). Only 52.7% and 56.2% of patients with HPV-positive OSCC felt they knew enough to be comfortable discussing HPV with their doctor or sexual partner, respectively. The most frequently used information source was the internet (80.9%), which ranked 8th in trust of 15 possible sources. Although most (95.5%) patients trusted information from their doctors, only 37.9% used doctors as an information source. CONCLUSIONS: Doctors are a highly trusted, but infrequent utilized, information source and should facilitate patient access to high-quality HPV information sources.

Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population.

OBJECTIVES: To examine the relationship between polymorphisms of the epidermal growth factor receptor (EGFR) pathway and toxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with cetuximab. MATERIAL AND METHODS: Multicenter, retrospective, observational pilot study which included 110 patients with histologically-confirmed human papillomavirus (HPV) negative HNSCC in locally advanced stages (III-IVA-B) and who were treated with chemotherapy and radiotherapy plus cetuximab between 2003 and 2013. Genetic analyses for single nucleotide polymorphisms (SNP) in genes EGFR, CCDN1, FCGR2A, FCGR3A and KRAS-LCS6 were performed though available allelic discrimination assay and/or polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: Acneiform rash was observed in 55.5% of patients, dry skin in 45.5% and pruritus in 20.9%. A significant association with dry skin and global cetuximab-related toxicity was observed for the KRAS-LCS6 (rs61764370) variant (p<0.05); carriers of the G allele (genotypes TG+GG) in the dominant model were observed to have a decreased susceptibility of developing dry skin (OR=0.287 [95%CI=0.119-0.695]). Carriers of the A (GA+AA) allele for EGFR (rs2227983) showed a decreased risk of suffering from pruritus (OR=0.345 [0.124-0.958]). Similarly, KRAS (rs1801274) was related with lower global cetuximab-related toxicity (OR=0.266 [0.114-0.622]). CONCLUSION: This pilot study provides preliminary evidence supporting genetic variation of EGFR (rs2227983), KRAS (rs61764370) and FCGR2A (rs180127) as useful biomarkers for predicting reduced skin toxicity in HNSCC patients treated with a cetuximab-based therapy. Alternative therapeutic options should be explored for these patients.

Epidemiological characteristics of a Spanish cohort of patients diagnosed with squamous cell carcinoma of head and neck: distribution of risk factors by tumor location

Purpose. Head and neck cancer is a highly heterogeneous disease comprising a large number of tumors located in the cervicofacial area. This study aimed to determine the epidemiological characteristics of squamous-cell carcinomas of the head and neck in the Spanish population, and the distribution of risk factors based on tumor locations. Methods/patients. A cohort of 459 patients (75 oral cavity, 167 oro-/hypopharyngeal and 217 laryngeal cancers) recruited in 19 hospitals participating in the Spanish head and neck cancer cooperative group were included over 3 years (2012-2014). Epidemiological parameters and risk factors were obtained from a self-administered questionnaire, and tumor characteristics were obtained from clinical records. Multivariate multinomial logistic regression was used to assess factors associated with tumor location. Results. Most patients were males (88.4 %), smokers (95 %) and drinkers (76.5 %). Relative to laryngeal cancer, pharyngeal cancer and oral cancer were more common in women than men (OR 3.58, p = 0.003 and 4.33, p = 0.001, respectively); pharyngeal cancer was more associated with rural environment (OR 1.81, p = 0.007) and weekly alcohol intake (10-140 g: OR 2.53, p = 0.012; 141-280 g: OR 2.47, p = 0.023; >280 g: OR 3.20, p = 0.001) and less associated with pack-years of smoking (21-40 packs: OR 0.46, p = 0.045; 41-70 packs: OR 0.43, p = 0.023; ≥71 packs: OR 3.20, p = 0.015). Conclusions. The distribution of these tumors differs between the sexes, with a higher proportion of oral cavity and pharyngeal tumors in women than in men. Oro-/hypopharyngeal cancers were more strongly associated with rural areas and with alcohol consumption, although less strongly associated with smoking than laryngeal tumors (AU)

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Residual neck disease management in squamous-cell carcinoma of the head and neck treated with radiotherapy plus cetuximab

Purpose. Management of residual neck disease (RND) is one of the unsolved points after bio-radiotherapy (BRT) in loco-regional advanced squamous-cell carcinoma of the head and neck (SCCHN). The aims of the study were to characterize the radiological pattern of response by computed tomography (CT) and to assess the role of positron-emission tomography (PET)/CT in this setting for a better decision-making in the indication of neck dissection (ND). Methods. We retrospectively reviewed 202 patients consecutively diagnosed with node-positive SCCHN (N1: 24; N2: 152; N3: 26) who had been treated with concomitant radiotherapy and cetuximab with or without previous induction chemotherapy between 2006 and 2013. Radiological evaluation after treatment was assessed by standard criteria using CT and in addition by PET/CT when RND was suspected in cases from 2010. Results. There were 42 (21 %) patients who achieved complete response of the primary tumor persisting RND by CT. From this group, 24 patients were managed without PET/CT, leading to the performance of ND in 22 (92 %). On the other hand, 18 patients underwent PET/CT and ND was performed in only 6 (33 %). The overall survival was not different between both groups (p = 0.32). After histological examination and follow-up, PET/CT obtained a positive predictive value of 56 % and a negative predictive value of 89 %. Conclusions. Radiological response after BRT is similar to that after treatment with chemo-radiotherapy, thereby validating in this scenario the accepted CT criteria to define complete response of the neck. However, when RND is suspected by CT, PET/CT is useful to prevent unnecessary ND (AU)

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Low etiologic fraction for human papillomavirus in larynx squamous cell carcinoma.

BACKGROUND: Human Papillomavirus (HPV) is a cause of oropharyngeal squamous cell carcinoma (OPSCC), but its pathogenic role in larynx squamous cell carcinoma (LSCC) remains unclear. MATERIAL AND METHODS: A single-institutional, retrospective case-series was performed to estimate the etiological fraction (EF) for HPV in LSCC. Eligible cases included 436 consecutive cases of LSCC diagnosed (2005-2014) at The Ohio State University Medical Center. HPV DNA presence was detected by consensus primer PCR (Inno-LiPa) and HPV type-specific qPCR. HPV E6/E7 mRNA expression was detected by type-specific qRT-PCR. Tumor p16 expression was evaluated by immunohistochemistry (IHC). RESULTS: HPV DNA was detected by Inno-LiPa in 54 of 404 (13.4%, 95% CI 10.2-17.1) evaluable samples but was confirmed by HPV type-specific qPCR in only 14 (3.5%, 95% CI 1.9-5.7). Only 7 of 404 (1.7%, 95% CI 0.7-3.5) LSCC were positive for HPV E6/E7 mRNA expression, including HPV16 (n=4) and 1 each for 11, 26 and 33. In the HPV11-positive tumor, Sanger sequencing discovered 6 nucleotide mutations in the upstream regulation region, E6 and E7. Of 404 LSCC, 18 had strong and diffuse p16 expression. In comparison to a gold standard of HPV E6/E7 mRNA expression, p16 expression had a sensitivity of 71.4% (95% CI 29.0-96.3), specificity of 96.7% (95% CI 94.5-98.3), positive-predictive-value (PPV) of 27.8% (95% CI 9.7-53.5) and negative-predictive-value of 99.5% (95% CI 98.1-99.9). CONCLUSION: The EF for HPV in LSCC is low (1.7%) in a geographic region with high EF for OPSCC. Low-risk HPV may rarely cause LSCC. Finally, p16 expression has poor PPV for HPV in LSCC.

Epidemiological characteristics of a Spanish cohort of patients diagnosed with squamous cell carcinoma of head and neck: distribution of risk factors by tumor location.

PURPOSE: Head and neck cancer is a highly heterogeneous disease comprising a large number of tumors located in the cervicofacial area. This study aimed to determine the epidemiological characteristics of squamous-cell carcinomas of the head and neck in the Spanish population, and the distribution of risk factors based on tumor locations. METHODS/PATIENTS: A cohort of 459 patients (75 oral cavity, 167 oro-/hypopharyngeal and 217 laryngeal cancers) recruited in 19 hospitals participating in the Spanish head and neck cancer cooperative group were included over 3 years (2012-2014). Epidemiological parameters and risk factors were obtained from a self-administered questionnaire, and tumor characteristics were obtained from clinical records. Multivariate multinomial logistic regression was used to assess factors associated with tumor location. RESULTS: Most patients were males (88.4 %), smokers (95 %) and drinkers (76.5 %). Relative to laryngeal cancer, pharyngeal cancer and oral cancer were more common in women than men (OR 3.58, p = 0.003 and 4.33, p = 0.001, respectively); pharyngeal cancer was more associated with rural environment (OR 1.81, p = 0.007) and weekly alcohol intake (10-140 g: OR 2.53, p = 0.012; 141-280 g: OR 2.47, p = 0.023; >280 g: OR 3.20, p = 0.001) and less associated with pack-years of smoking (21-40 packs: OR 0.46, p = 0.045; 41-70 packs: OR 0.43, p = 0.023; ≥71 packs: OR 3.20, p = 0.015). CONCLUSIONS: The distribution of these tumors differs between the sexes, with a higher proportion of oral cavity and pharyngeal tumors in women than in men. Oro-/hypopharyngeal cancers were more strongly associated with rural areas and with alcohol consumption, although less strongly associated with smoking than laryngeal tumors.

Residual neck disease management in squamous-cell carcinoma of the head and neck treated with radiotherapy plus cetuximab.

PURPOSE: Management of residual neck disease (RND) is one of the unsolved points after bio-radiotherapy (BRT) in loco-regional advanced squamous-cell carcinoma of the head and neck (SCCHN). The aims of the study were to characterize the radiological pattern of response by computed tomography (CT) and to assess the role of positron-emission tomography (PET)/CT in this setting for a better decision-making in the indication of neck dissection (ND). METHODS: We retrospectively reviewed 202 patients consecutively diagnosed with node-positive SCCHN (N1: 24; N2: 152; N3: 26) who had been treated with concomitant radiotherapy and cetuximab with or without previous induction chemotherapy between 2006 and 2013. Radiological evaluation after treatment was assessed by standard criteria using CT and in addition by PET/CT when RND was suspected in cases from 2010. RESULTS: There were 42 (21 %) patients who achieved complete response of the primary tumor persisting RND by CT. From this group, 24 patients were managed without PET/CT, leading to the performance of ND in 22 (92 %). On the other hand, 18 patients underwent PET/CT and ND was performed in only 6 (33 %). The overall survival was not different between both groups (p = 0.32). After histological examination and follow-up, PET/CT obtained a positive predictive value of 56 % and a negative predictive value of 89 %. CONCLUSIONS: Radiological response after BRT is similar to that after treatment with chemo-radiotherapy, thereby validating in this scenario the accepted CT criteria to define complete response of the neck. However, when RND is suspected by CT, PET/CT is useful to prevent unnecessary ND.

[Degree of public awareness regarding intensive care units (ICUs) and intensive care physicians in Castilla y León]. / Nivel de conocimiento sobre las unidades de cuidados intensivos (UCI) y los médicos intensivistas entre los ciudadanos de Castilla y León.

AIM: To determine degree of public awareness regarding the activities and health care professionals that comprise intensive care units (ICUs) in the autonomous community of Castilla y León. DESIGN: Questionaire in the form of a true-false test dealing with a) description of an ICU; b) description of ICU patients, and c) degrees and qualifications held by ICU physicians. LOCATION: Waiting rooms of outpatient clinics and ICUs of 9 hospitals in Castilla y León. SUBJECTS AND METHODS: During the period from 1 October 2003 to 29 February 2004, there were surveyed a group of those persons accompanying outpatients arriving for appointments (OP, n = 2,293), and a group comprised of relatives of ICU patients (ICU, n = 727) upon discharge from the ICU. RESULTS: The average age of those subjects surveyed was 45.6 years old. 62.1% were women and 52.8% had received education through secondary level or higher. Of the 1,354 analyzed OP questionnaires, 27.7%, 25.5% and 48.4% responded correctly to questions A, B and C, respectively. Of the 284 analyzed ICU questionnaires, 38.6%, 41.0%, and 63.5% responded correctly to questions A, B and C, respectively. Differences between results from the two surveyed groups were statistically significant, and the best results from the ICU group were found among those subjects whose family members had remained in ICU for 2 days or more. CONCLUSIONS: In the described scope, of the citizens of Castilla y León, 27.7% know as it is a ICU, 25.5% know what type of patients usually is entered there, and 48.4% recognize their doctors like ICU specialists specifically. These knowledge improve significantly after having some relative entered in ICU for more than 2 days.